Bladder cancer is a leading cause of death worldwide. Most of the patients who present with superficial bladder cancer tumours will experience a recurrence within 5 years and almost 90% of these patients will have a recurrence within 15 years.
Haematuria, which refers to the presence of blood in urine, is a presenting symptom for a variety of diseases, including bladder cancer. The number of patients presenting with haematuria is progressively increasing in our aging population and the diagnosis of serious diseases in some of these patients can be delayed when triage is ineffective[1]. Therefore new risk stratification approaches are needed.
The final diagnosis for haematuria patients ranges from no diagnosis, through benign conditions including urinary infection, stone disease, benign prostate enlargement (BPE) to renal diseases and malignant causes. Urothelial cancer (UC), also known as transitional cell carcinoma (TCC), is the most common malignancy in haematuric patients and is the fourth most common cancer in men. UC was the estimated cause of death in 150,200 people, worldwide in 2008[3].
Bladder cancer is associated with many risk factors, for example its development is three times more common in men than in women[2]. However, this gender disparity is largely historical and is related to smoking habits. Smoking increases the risk of UC four-fold and cessation of smoking is associated with a decreased risk. Although UC is associated with smoking and carcinogen exposure, bladder cancers that arise following chronic inflammation are usually squamous cell carcinomas[2].
At the time of diagnosis, approximately 70% of patients diagnosed with UC have tumours that are pathologically staged as pTa, pT1 or carcinoma in situ (CIS) i.e., non-muscle invasive (NMI) disease and these patients can have a good prognosis. When a patient's tumour is pathologically defined as ≧T1G3 UC, the patient is deemed to have a high risk of progression to a more life threatening disease[2, 4]. Muscle invasive UC (MI UC) encompasses all pathological stages pT2. The risk parameters that are currently used to tailor follow-up for patients diagnosed with UC, include pathological parameters i.e., grade, stage and associated CIS, together with resistance to Bacille Calmette-Guerin treatment. However, it is not always possible to correctly predict the outcome for patients. This is largely attributable to the molecular heterogeneity within tumours which means that a spectrum of outcomes, spanning from negligible risk to life threatening prognosis, exists within the same pathologically classified groups. For this reason, all patients with NMI disease have frequent surveillance cystoscopies and those with MI have radiological surveillance for lymph node recurrence or distant metastasis[2].
Cystoscopy is the gold standard for the detection and surveillance of NMI UC[2]. However, this procedure is costly for health services and invasive for the patient. Furthermore, it requires a significant clinical input and has its own shortcomings[2, 5].
Cytology, another diagnostic test for bladder cancer, detects the presence of malignant cells in urine. Although cytology has high specificity, it has insufficient sensitivity to stand alone as a diagnostic test for UC in patients presenting with haematuria[2].
Despite their approval by the Food and Drug Administration (FDA), three diagnostic bladder cancer biomarkers, Nuclear Matrix Protein 22[6], Bladder Tumour Antigen (BTA)[7] and Fibrinogen Degradation Product[8], are not in use in routine practise as diagnostic biomarkers for UC because of their limited specificity. There is therefore a strong clinical need for urine-based tests which can at least risk stratify, and if possible, be diagnostic in haematuric patients[2].
Researchers often combine multiple tests, genes or biomarkers[9-11]. However, it is not possible to intuitively predict how multiple measurements, will collectively reflect the underlying biological heterogeneity in complex diseases, such as UC. Complex diseases consist of multiple components which interact to produce emergent properties that the individual components do not possess.
Therefore, there is a need for new approaches to identifying patients who are at risk of serious disease. It would be beneficial to enable clinicians to interpret risk classifiers alongside other clinical information at the time of triage, in order to reduce the number of cystoscopies and enable priority diagnosis of aggressive UC and other serious diseases, resulting in improved patient outcomes at reduced costs.